Preeclampsia is a hypertensive, multi-system disorder of pregnant women that affects approximately 6% of first pregnancies and 1-2% of all pregnancies (MacGillivary, I., Preeclampsia: the hypertensive disease of pregnancy. W.B. Saunders, Philadelphia 1987:17). Preeclampsia is a major cause of maternal and fetal mortality and morbidity, and is a disease unique to human beings during pregnancy. Hospitalization, strict bed rest, magnesium sulfate administration to prevent convulsions, and prompt delivery remain the current standard of therapy for preeclampsia. Complications of preeclampsia include eclamptic seizures, hemolysis, elevated liver function tests, low platelet count (HELLP) syndrome, hepatic rupture, DIC pulmonary edema, acute renal failure, placental abruption, intrauterine fetal demise (IUFD), cerebral hemorrhage, cortical blindness, and retinal detachment. Despite many years of study, the causes of preeclampsia are unclear.
The hallmarks of preeclampsia include hypertension, proteinuria, and edema. Underlying these clinical manifestations, placental maladaptation and body-wide endothelial cell dysfunction occur (Khong, T. Y. et al. (1986) Br. J. Obstet. Gynecol. 93:1049-1059; Roberts, J. M. et al. (1991) Am. J. Hypertens. 4:700-708). Failure of trophoblastic invasion into myometrial segments of maternal spiral arteries and the production of cytotoxic mediators which cause systemic endothelial damage also seem to be implicated.
During normal development human trophoblasts invade through the extracellular matrix into the myometrial portion of spiral arteries and convert them into uteroplacental arteries (Pijnenborg et al., in Trophoblast Research (Denker and Aplin, eds.) Plenum Press, New York, p. 333 (1990)). Uteroplacental arteries then dilate approximately 30-fold as large as the spiral arteries. Resulting hemodynamic changes enable the placental bed to satisfy the increased demand for oxygen from the fetus during the latter stages of gestation. In preeclamptic women, however, spiral arteries are not properly converted into uteroplacental arteries due to the failure of the second wave of trophoblastic migration into the myometrium at the beginning of the second trimester (Khong et al. (1986) Br. J. Obstet. Gynecol. 93:1049-1059). As a result, preeclamptic women typically demonstrate a high-resistance, high-pressure, and low-flow state with intact, non-dilated spiral arteries (Robertson et al. (1986) Am. J. Obstet. Gynecol. 155:401-412), and demonstrate a wide variety of clinical syndromes.
Preeclampsia may be divided into mild and severe forms. Mild preeclampsia is indicated where the patient exhibits hypertension, a proteinuria level of greater than 300 mg per 24 hour period, mild edema signaled by weight gain of greater than 2 pounds per week or 6 pounds per month, and urine output of less than 500 ml per 24 hour period. Severe preeclampsia is indicated where the patient's blood pressure is greater than 160/110 on two occasions at least six hours apart while on bed rest or a systolic blood pressure increase of greater than 60 over a baseline value or a diastolic increase of greater than 30. In addition, a proteinuria level of greater than 5 g per 24 hour period or a reading of 31 or 41 on a urine dipstick, massive edema, oliguria (less than 400 ml per 24 hour period), presence of fetal growth retardation (IUGR), or systemic symptoms including pulmonary edema, headaches, visual changes, right upper quadrant pain, elevated liver enzymes or thrombocytopenia.
After a diagnosis of preeclampsia, the baby is generally induced and delivered if it is near term, i.e., after 36 weeks. However, if preeclampsia occurs earlier in the pregnancy, its impact is more profound. The only “cure” for the disease is delivery of the baby, which is generally contrary to the best interests of the baby if it is not near term. However, if the condition does not respond to traditional management options, early delivery may be the only option remaining. Traditional management includes bed rest, antihypertensive therapy, including methyldopa (Aldomet™), atenolol, and labetalol. If the term of pregnancy from the diagnosis of preeclampsia to delivery could be extended safely for both the fetus and mother, then significant improvement in perinatal outcomes may be achieved.
It is therefore an object of the present invention to overcome these shortcomings in existing treatments for preeclampsia by providing safe and effective methods and compositions for the treatment of preeclampsia and other pregnancy related disorders.